Clavulanic acid: A competitive inhibitor of beta-lactamases with novel anxiolytic-like activity and minimal side effects

Kim, Deog J.; King, Jean A.; Zuccarelli, Lisa A.; Ferris, Craig F.; Koppel, G. A.; Snowdon, Charles T.; Ahn, Chang Ho

doi:10.1016/j.pbb.2009.04.013

Cited by 36 publications

(37 citation statements)

References 36 publications

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“…Clavulanic acid also has a β-lactam structure with negligible intrinsic antibacterial activity and it crosses the BBB very easily, achieving a CSF/plasma ratio of ~0.25 (Nakagawa et al, 1994). It also appears to have anxiolytic effects in primates and rodents (Kim et al, 2009). In addition, clavulanic acid appears to have anti-seizure properties, at least in invertebrates (Rawls et al, 2010), although it is unclear whether this anti-seizure effect of clavulanic acid was due to its ability to enhance glutamate uptake or not.…”

Section: Discussionmentioning

confidence: 99%

Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

et al. 2015

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Studies have shown that administration of the β-lactam antibiotic, ceftriaxone (CEF) attenuates ethanol consumption and cocaine seeking behavior as well as preventing ethanol-induced downregulation of glutamate transporter 1 (GLT-1) expression in central reward brain regions. However, it is not known if these effects are compound-specific. Therefore, the present study examined the effects of two other β-lactam antibiotics, amoxicillin (AMOX) and amoxicillin/clavulanate (Augmentin, AUG), on ethanol drinking, as well as GLT-1 and phosphorylated-AKT (pAKT) levels in the nucleus accumbens (Acb) and medial prefrontal cortex (mPFC) of alcohol-preferring (P) rats. P rats were exposed to free-choice of ethanol (15% and 30%) for five weeks and were given five consecutive daily i.p. injections of saline vehicle, 100 mg/kg AMOX or 100 mg/kg AUG. Both compounds significantly decreased ethanol intake and significantly increased GLT-1 expression in the Acb. AUG also increased GLT-1 expression in the mPFC. Results for changes in pAKT levels matched those for GLT-1, indicating that β-lactam antibiotic-induced reductions in ethanol intake are negatively associated with increases in GLT-1 and pAKT levels within two critical brains regions mediating drug reward and reinforcement. These findings add to a growing literature that pharmacological increases in GLT-1 expression are associated with decreases in ethanol intake and suggest that one mechanism mediating this effect may be increased phosphorylation of AKT. Thus, GLT-1 and pAKT may serve as molecular targets for the treatment of alcohol and drug abuse/dependence.

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Section: Discussionmentioning

confidence: 99%

Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

et al. 2015

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“…Some of the effects of CTX are prevention of analgesic tolerance and physical dependence that develops during chronic morphine exposure (Rawls et al, 2007, 2010a, b), inhibition of opioid-induced hyperalgesia (Chen et al, 2012), inhibition of relapse to cocaine seeking (Knackstedt et al, 2010; Sari et al, 2009), inhibition of the direct reinforcing effects of cocaine in mice maintained under a progressive-ratio responding schedule (Ward et al, 2011), inhibition of locomotor sensitization produced by cocaine and amphetamine (Tallarida et al, 2013; Sondheimer and Knackstedt, 2011; Rasmussen et al, 2011), prevention of methamphetamine-induced CPP (Abulseoud et al, 2013), and reduction of alcohol consumption (Sari et al, 2013; Rao and Sari, 2012). Despite structural similarities between CA and CTX, and the more favorable pharmacokinetic and physiochemical properties of CA as related to CNS activity (Nakagawa et al, 1994; Bolton et al, 1986), the potential effectiveness of CA as a therapeutic for CNS diseases is limited to studies that have examined neuroprotection, anxiety, and erectile dysfunction (Kim et al, 2009; Kost et al, 2011, 2012; Sanna et al, 2013). To our knowledge, the present results are the first evidence that CA can disrupt rewarding and sensitizing effects of an addictive substance.…”

Section: Discussionmentioning

confidence: 99%

“…This dosing paradigm was used because multiple laboratories have demonstrated that the preclinical activity of CTX in reducing the symptoms of CNS diseases is dependent on repeated administration (Rothstein et al, 2005; Sari et al, 2009, 2013; Rawls et al, 2007, 2010a, b; Tallarida et al, 2013; Trantham-Davidson et al, 2012). In contrast to our dosing schedule, the in vivo studies showing that CA increases dopamine transmission have used a design in which CA was injected once (Kim et al, 2009; Sanna et al, 2013). Though speculative, it could be that monoamine transmission is augmented following acute CA exposure and that glutamate uptake is enhanced following chronic exposure to CA.…”

Section: Discussionmentioning

confidence: 99%

“…Both compounds contain a central β-lactam ring required for enhancement of cellular glutamate reuptake through activation of glutamate transporter subtype 1 (GLT-1), which is thought to be a primary reason for the efficacy of CTX in animal models of CNS diseases (Rothstein et al, 2005). Relative to CTX, CA displays a number of desirable properties related to CNS activity, including negligible antibacterial activity, oral bioavailability (64-75%), and enhanced brain penetrability evident from a cerebrospinal fluid/plasma ratio of around 0.25 in patients with intact meninges (Kim et al, 2009; Nakagawa et al, 1994; Bolton et al, 1986). …”

Section: Introductionmentioning

confidence: 99%

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Clavulanic acid reduces rewarding, hyperthermic and locomotor-sensitizing effects of morphine in rats: A new indication for an old drug?

Schroeder

Tolman

McKenna

et al. 2014

Drug and Alcohol Dependence

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Background Despite the efficacy of ceftriaxone (CTX) in animal models of CNS diseases, including drug addiction, its utility as a CNS-active therapeutic may be limited by poor brain penetrability and cumbersome parenteral administration. An alternative is the β-lactamase inhibitor clavulanic acid (CA), a constituent of Augmentin that prevents antibiotic degradation. CA possesses the β-lactam core necessary for CNS activity but, relative to CTX, possesses: 1) oral activity; 2) 2.5-fold greater brain penetrability; and 3) negligible antibiotic activity. Methods To compare the effectiveness of CA (10 mg/kg) and CTX (200 mg/kg) against centrally-mediated endpoints, we investigated their effects against morphine’s rewarding, hyperthermic, and locomotor-sensitizing actions. Endpoints were based on prior evidence that CTX attenuates morphine-induced physical dependence, tolerance, and hyperthermia. Results As expected, rats treated with morphine (4 mg/kg) displayed hyperthermia and conditioned place preference (CPP). Co-treatment with CTX or CA inhibited development of morphine-induced CPP by approximately 70%. Morphine’s hyperthermic effect was also suppressed, with CTX and CA producing 57% and 47% inhibition, respectively. Locomotor sensitization induced by repeated morphine exposures was inhibited by CA but not CTX. Conclusions The present findings are the first to suggest that CA disrupts the in vivo actions of morphine and point toward further studying CA as a potential therapy for drug addiction. Further, its ability to disrupt morphine’s rewarding effects at 20-fold lower doses than CTX identifies CA as an existing, orally-active alternative to direct CTX therapy for CNS diseases.

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“…CA is structurally similar to CTX with both compounds having a central β-lactam pharmacophore required for activation of GLT-1 transporters (Rothstein et al 2005). The potential advantage of CA relative to CTX is a more desirable therapeutic profile, including greater oral bioavailability (64–75 %), enhanced brain penetrability evident from a cerebrospinal fluid/plasma ratio of around 0.25 in patients with intact meninges, and negligible antibacterial activity (Bolton et al 1986; Nakagawa et al 1994; Kim et al 2009). Based on evidence that CTX reduces cocaine self-administration (SA) in rats and mice, and structural similarities between CTX and CA and enhanced brain penetrability of CA, we hypothesized that CA would reduce the reinforcing strength of cocaine in a mouse model of SA and increase GLT-1 transporter expression in the nucleus accumbens, but at lower doses than CTX.…”

Section: Introductionmentioning

confidence: 99%

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

et al. 2015

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The β-lactam antibiotic ceftriaxone (CTX) reduces cocaine reinforcement and relapse in preclinical assays through a mechanism involving activation of glutamate transporter subtype 1 (GLT-1). However, its poor brain penetrability and intravenous administration route may limit its therapeutic utility for indications related to CNS diseases. An alternative is clavulanic acid (CA), a structural analog of CTX that retains the β-lactam core required for GLT-1 activity but displays enhanced brain penetrability and oral activity relative to CTX. Here, we tested the hypothesis that CA (1, 10 mg/kg ip) would enhance GLT-1 expression and decrease cocaine self-administration (SA) in mice, but at lower doses than CTX. Experiments revealed that GLT-1 transporter expression in the nucleus accumbens of mice treated with repeated CA (1, 10 mg/kg) was enhanced relative to saline-treated mice. Repeated CA treatment (1 mg/kg) reduced the reinforcing efficacy of cocaine (0.56 mg/kg/inf) in mice maintained on a progressive-ratio (PR) schedule of reinforcement but did not affect acquisition of cocaine SA under fixed-ratio responding or acquisition or retention of learning. These findings suggest that the β-lactamase inhibitor CA can activate the cellular glutamate reuptake system in the brain reward circuit and reduce cocaine’s reinforcing efficacy at 100-fold lower doses than CTX.

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Clavulanic acid: A competitive inhibitor of beta-lactamases with novel anxiolytic-like activity and minimal side effects

Cited by 36 publications

References 36 publications

Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

Amoxicillin and amoxicillin/clavulanate reduce ethanol intake and increase GLT-1 expression as well as AKT phosphorylation in mesocorticolimbic regions

Clavulanic acid reduces rewarding, hyperthermic and locomotor-sensitizing effects of morphine in rats: A new indication for an old drug?

Clavulanic acid enhances glutamate transporter subtype I (GLT-1) expression and decreases reinforcing efficacy of cocaine in mice

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